Diagnosis and management of von Willebrand disease: A community-wide effort to deliver evidence-based clinical practice guidelines.

Abstract

HaemophiliaVolume 27, Issue 2 p. 181-183 COMMENTARYFree Access Diagnosis and management of von Willebrand disease: A community-wide effort to deliver evidence-based clinical practice guidelines Barbara A. Konkle, Corresponding Author Barbara A. Konkle barbarak@bloodworksnw.org orcid.org/0000-0002-3959-8797 World Federation of Hemophilia, Montréal, QC, Canada Department of Medicine, University of Washington, Seattle, WA, USA Correspondence Barbara A. Konkle, Bloodworks Northwest, 921 Terry Avenue, 98104 Seattle, WA, USA. Email: barbarak@bloodworksnw.orgSearch for more papers by this authorSteven W. Pipe, Steven W. Pipe orcid.org/0000-0003-2558-2089 National Hemophilia Foundation, New York, NY, USA Departments of Pediatrics and Pathology, University of Michigan, Ann Arbor, MI, USASearch for more papers by this author Barbara A. Konkle, Corresponding Author Barbara A. Konkle barbarak@bloodworksnw.org orcid.org/0000-0002-3959-8797 World Federation of Hemophilia, Montréal, QC, Canada Department of Medicine, University of Washington, Seattle, WA, USA Correspondence Barbara A. Konkle, Bloodworks Northwest, 921 Terry Avenue, 98104 Seattle, WA, USA. Email: barbarak@bloodworksnw.orgSearch for more papers by this authorSteven W. Pipe, Steven W. Pipe orcid.org/0000-0003-2558-2089 National Hemophilia Foundation, New York, NY, USA Departments of Pediatrics and Pathology, University of Michigan, Ann Arbor, MI, USASearch for more papers by this author First published: 09 February 2021 https://doi.org/10.1111/hae.14262AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Von Willebrand disease (VWD) is the most common inherited bleeding disorder; it is estimated that between 1 in 1,000 and 1 in 10,000 people are affected by symptomatic bleeding, yet many patients go years without an accurate diagnosis while living with untreated bleeding.1-5 A lack of awareness of the difference between normal and abnormal bleeding symptoms coupled with the limited availability of specialized laboratory testing makes the diagnosis of VWD challenging.6-9 The clinical complexity of VWD and the absence of extensive evidence to guide decision-making means that there is considerable variability in the clinical management of the disorder. It is precisely in the context of inadequate awareness, variability in clinical practice, and a paucity of high-quality evidence in the published literature that clinical practice guidelines are most needed. In 2015, the World Federation of Hemophilia (WFH) VWD and Rare Bleeding Disorders Committee presented a proposal to the WFH Medical Advisory Board for the development of VWD guidelines. Simultaneously, the National Hemophilia Foundation (NHF) issued a report from their Strategic Summit on VWD that called for ‘A well-qualified and authoritative organization, or a consortium of such organizations, [to] develop a new or updated evidence-based clinical practice guideline on VWD’. The American Society of Hematology (ASH) and the International Society on Thrombosis and Haemostasis (ISTH) reached the same conclusions and in 2017 the four organizations came together in an unprecedented international collaboration to develop guidelines on VWD.10, 11 The strongest clinical practice guidelines are developed through a rigorous evidence-based process involving experts in diagnosing, treating and living with a disorder.12, 13 The ASH ISTH NHF WFH 2021 Guidelines on the Diagnosis and Management of VWD are based upon a systematic review and GRADEing of available literature and set a new standard for patient involvement in guideline development.10, 11 While previous VWD guidelines lacked any patient involvement, people with VWD made up approximately a quarter of both the Diagnosis and Management Panels. As full voting members, their voices carried equal weight to those of clinicians and researchers from GRADEing evidence to discussions of equity, cost-effectiveness, resource utilization, acceptability, feasibility, and patients' values and preferences, for each recommendation. The collaborating organizations contributed to trainings that prepared and empowered the patient panellists. Involvement of the global VWD community bookended this guideline development process. At the outset, a trilingual stakeholder survey provided the foundation for the prioritization of clinical questions to be addressed. The overwhelming response to this survey (over 9,500 comments from over 600 participants, equal proportions of people with VWD and healthcare professionals, from 71 countries) merited its own publication14 and underscored the urgent need for VWD guidelines. Two years later, over 100 individuals (approx. 15% patients and caregivers) from nearly 40 countries provided public comment on the draft guidelines. This appetite for tools to improve the diagnosis, management, and quality of life of people with VWD and the enthusiastic participation in initiatives to generate these tools, hopefully, bode well for the adoption and adaptation of these guidelines throughout the world. The clinical manifestations of VWD may touch every aspect of an affected person's life. Thus, these guidelines are relevant to their interactions with all healthcare professionals, not just those specializing in the diagnosis and management of bleeding disorders. General practitioners, emergency physicians, dentists, internists, surgeons, gynaecologists, obstetricians, anaesthetists, and many more will do well to familiarize themselves with these guidelines. The 11 diagnosis recommendations cover: The role of bleeding assessment tools (BAT) in the assessment of patients suspected of VWD Diagnostic laboratory cut-offs for type 1 and type 2 VWD The role of genetic testing vs. phenotypic assays for types 2B and 2 N The reconsideration, rather than simple removal, of a type 1 VWD diagnosis, should VWF levels normalize over time The eight management recommendations cover: Prophylaxis for severe and frequent bleeds Desmopressin (DDAVP) trials to determine therapy Use of antithrombotic therapy (antiplatelet agents and anticoagulant therapy) Target VWF and factor VIII activity levels for major surgery Strategies to reduce bleeding during minor surgery or invasive procedures Management options for heavy menstrual bleeding Management of VWD in the context of neuraxial anaesthesia during labour and delivery Management in the postpartum setting A number of recommendations align with existing publications15, 16 with the added value of a thorough evaluation of the evidence supporting them, while others provide important new guidance. The Diagnosis Panel placed a high value on not missing the diagnosis of affected individuals in order to ensure access to care. This is reflected throughout the recommendations and exemplified in the cut-off recommended for the diagnosis of type 1, where a patient's bleeding symptoms were the primary consideration. Similarly, patient values, preferences and access to care were important considerations when recommending a reconsideration, rather than a simple dismissal, of a type 1 VWD diagnosis in patients whose VWF levels normalize over time. The comprehensive but clear diagnostic algorithms provided in the figures of the Diagnosis Guidelines will assist professionals in tackling this complex decision tree. The Management Guidelines also place a consistent emphasis on seeking optimal outcomes for individuals affected by abnormal bleeding. The recommendation of prophylaxis for frequent and severe bleeds does not specify a VWD subtype, and the recommendations on the management of heavy menstrual bleeding point out that some women and girls may need prophylaxis to control bleeding. While VWD is inherited equally by men and women, women are disproportionately impacted by menstrual and postpartum haemorrhage. The particular need for guidance on issues specific to women's health was highlighted in the responses (of both men and women) to the stakeholder clinical question prioritization survey14 and is reflected in the multiple recommendations devoted to heavy menstrual bleeding, neuraxial anaesthesia and postpartum management. Bleeding symptoms specific to women are also considered in the recommendations on the use of BATs in the Diagnosis Guidelines. Like most clinical practice guidelines, these guidelines face the limitation that they simply cannot cover every topic for which guidance is needed. The prioritization process was valid and informed by many and varied perspectives, but some will invariably find that their most pressing concern did not make the cut. This is unavoidable and may even serve to spur other organizations to contribute similarly developed guidelines on some of these topics. Similarly, as the knowledge base evolves it will be important to update these guidelines, employing an equally rigorous and collaborative process. Globally, the biggest barrier to the implementation of many of the recommendations for both management and diagnosis of VWD will be the resources required. The Diagnosis Panel was cognizant of the lack of uniform availability of some of the assays that it recommends, and the expertise they require, while the Management Panel considered the resources required and limitations on access to many treatment options in their deliberations. These restrictions are present in developed countries in regard to the availability and access to specialized diagnostic tests (and the facilities and expertise to perform them) and treatment options vary greatly within and between countries. In developing countries, the challenges are much greater. While some of the recommendations can and should be adopted as aspirational targets and the focus of advocacy efforts with the weight of the ASH ISTH NHF WFH 2021 Guidelines behind them, others will be simply out of reach. The guideline authors recognize this reality and invite adaptations to local circumstances, based on the associated Evidence-to-Decision frameworks,17 the details of which are all available in the supplementary materials of the two publications.10, 11 As the community is aware, we lack published prospective studies conducted on large groups of patients with consistently defined outcome assessments and rigorous controls. That the evidence to support the ASH ISTH NHF WFH 2021 Guidelines on the Diagnosis and Management of VWD recommendations was frequently GRADEd as offering low or even very low certainty is an honest indictment of the situation. It should not point to a weakness of the recommendations, however. The detailed summaries of the evidence in the publications and the Evidence-to-Decision framework tables allow those so inclined to conduct a similar analysis and reach their own conclusions. Assuredly, the recommendations presented in the publications are the results of careful deliberation and consideration and constitute the best advice available today. Importantly, the panels provided detailed lists of the most pressing areas of further research for each recommendation. Hopefully, the coming years will see these lists frequently consulted and progressively diminished fuelling additional and updated evidence-based guidelines. The publication of these guidelines is only the beginning of the quest to support patients, clinicians and healthcare professionals in their shared decision-making about VWD. In this next phase of dissemination, education, implementation and advocacy, the VWD community will be well served by the continued international collaboration between four important organizations (ASH, ISTH, NHF and WFH), the integral involvement of people with VWD, and the genuine dedication of the healthcare professional panellists to the community. Educational resources that make this information accessible to people with VWD will be important in achieving the shared decision-making recommended by the guidelines. Clinical webinars, multilingual short summaries, decision aids, patient-oriented materials and more will feature in the work of all four organizations in the coming months and years. Advocacy efforts, such as the proposal to include subtypes of VWD in the International Classification of Disease, Tenth Revision, Clinical Modification, to facilitate patient care and research, are already underway and many more must follow. The bleeding disorders community must be creative and resourceful as educational and awareness-raising campaigns must reach groups not always targeted by traditional outreach, in both the healthcare and public spheres. ACKNOWLEDGEMENTS The authors thank Mark W Skinner, Ellen Riker and Fiona Robinson for serving as the representatives of the NHF and WFH in the VWD guidelines collaboration and for their thoughtful input on this Commentary. The authors thank the ASH ISTH NHF WFH 2021 Guidelines on the Diagnosis and Management of VWD authors for sharing, in confidence, the draft manuscripts prior to publication in order to inform this Commentary. DISCLOSURES BAK has acted as a paid consultant for Biomarin, CSL Behring, Pfizer, Sanofi, and Sigilon and has received research funding from Pfizer, Sanofi, Sigilon, Takeda, Roche and uniQure. SWP has received consulting fees from Apcintex, Bayer, Biomarin, Catalyst Biosciences, CSL Behring, HEMA Biologics, Freeline, Novo Nordisk, Pfizer, Roche/Genentech, Sangamo Therapeutics, Sanofi, Takeda, Spark Therapeutics and uniQure. Open Research DATA AVAILABILITY STATEMENT Data sharing not applicable – no new data generated. REFERENCES 1Bowman M, Hopman WM, Rapson D, Lillicrap D, James P. The prevalence of symptomatic von Willebrand disease in primary care practice. J Thromb Haemost. 2010; 8(1): 213- 216. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 2Bowman M, Hopman WM, Rapson D, Lillicrap D, Silva M, James P. A prospective evaluation of the prevalence of symptomatic von Willebrand disease (VWD) in a pediatric primary care population. 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